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Role of Self-Association and Supersaturation in Oral Absorption of a Poorly Soluble Weakly Basic Drug

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Abstract

Purpose

Precipitation of weakly basic drugs in intestinal fluids can affect oral drug absorption. In this study, the implications of self-association of brivanib alaninate in acidic aqueous solution, leading to supersaturation at basic pH condition, on its solubility and oral absorption were investigated.

Methods

Self-association of brivanib alaninate was investigated by proton NMR spectroscopy, surface tension measurement, dynamic light scattering, isothermal titration calorimetry, and molecular modeling. Drug solubility was determined in various pH media, and its tendency to supersaturate upon pH shift was investigated in buffered and biorelevant aqueous solutions. Pharmacokinetic modeling of human oral drug absorption was utilized for parameter sensitivity analyses of input variables.

Results

Brivanib alaninate exhibited continuous, and pH- and concentration-dependent self-association. This phenomenon resulted in positive deviation of drug solubility at acidic pH and the formation of a stable supersaturated drug solution in pH-shift assays. Consistent with the supersaturation phenomenon observed in vitro, oral absorption simulations necessitated invoking long precipitation time in the intestine to successfully predict in vivo data.

Conclusions

Self-association of a weakly basic drug in acidic aqueous solution can increase its oral absorption by supersaturation and precipitation resistance at the intestinal pH. This consideration is important to the selection of parameters for oral absorption simulation.

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Abbreviations

G+:

GastroPlus

ITC:

Isothermal titration calorimetry

NMR:

Nuclear magnetic resonance

tppt :

Precipitation time

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ACKNOWLEDGMENTS AND DISCLOSURES

We thank Judy Lin for analytical method development and validation; Gabriella Siryj and Denette Murphy for powder X-ray diffraction; and BMS Exploratory Clinical and Translational Research (ECTR) team for human pharmacokinetic data.

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Authors and Affiliations

  1. Drug Product Science and Technology, One Squibb Dr., New Brunswick, New Jersey, 08901, USA

    Ajit S. Narang, Sherif Badawy, Dhaval Patel, Maria Vincent, Krishnaswamy Raghavan, Balvinder Vig, John Crison, George Derbin, Yan Xu & Michael Galella

  2. Analytical and Bioanalytical Development, One Squibb Dr., New Brunswick, New Jersey, 08901, USA

    Qingmei Ye, Yande Huang & Frank A. Rinaldi

  3. Chemical Development, Bristol-Myers Squibb, Co., One Squibb Dr., New Brunswick, New Jersey, 08901, USA

    Antonio Ramirez

  4. Protein Science and Structure, Bristol-Myers Squibb, Co., Route 206 and Province Line Road, Princeton, New Jersey, 08543, USA

    Aaron Yamniuk

Authors
  1. Ajit S. Narang
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  2. Sherif Badawy
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  3. Qingmei Ye
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  4. Dhaval Patel
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  5. Maria Vincent
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  7. Yande Huang
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  8. Aaron Yamniuk
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  11. George Derbin
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  12. Yan Xu
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Correspondence to Ajit S. Narang.

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Narang, A.S., Badawy, S., Ye, Q. et al. Role of Self-Association and Supersaturation in Oral Absorption of a Poorly Soluble Weakly Basic Drug. Pharm Res 32, 2579–2594 (2015). https://doi.org/10.1007/s11095-015-1645-y

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  • DOI: https://doi.org/10.1007/s11095-015-1645-y

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